Henry, E. R. | bioRxiv Science

bioRxiv2022

A large nuclear and mitochondrial sequence dataset for phylogenetic analysis of the hyperdiverse Asterophryinae frogs of the New Guinea region with data on lifestyle, GPS coordinates, elevation, and multispecies communities with accompanying code

The data provided here is related to the article "Resolving the Deep Phylogeny: Implications for Early Adaptive Radiation, Cryptic, and Present-day Ecological Diversity of Papuan Microhylid Frogs" [1]. The dataset is based on 233 tissue samples of the subfamily Asteroprhyinae, with representatives from all recognized genera, in addition to three outgroup taxa. The sequence dataset contains over 2400 characters per sample for five genes (three nuclear loci: BDNF, NXC-1, and SIA; and two mitochondrial loci: ND4 and CYTB) and is 99% complete. New primers were designed for all loci and accession numbers for the raw sequence data are provided. The sequences are used with geological time calibrations to produce time-calibrated Bayesian inference and Maximum Likelihood phylogenetic reconstructions using BEAST2 and IQTREE. Lifestyle data (arboreal, scansorial, terrestrial, fossorial, semi-aquatic) were collected from the literature and field notes and used to infer ancestral character states for each lineage. Collection location data (GPS and elevation data) were used to verify sites where multiple species or candidate species co-occur. All sequence data, alignments, and associated metadata (voucher specimen number, species identification, type locality status, GPS, elevation, site with species list, and lifestyle) as well as the code to produce all analyses and figures are provided.

evolutionary biology↗

bioRxiv2022

Phenotypic screening of the ReFrame Drug Repurposing Library to discover new drugs for treating sickle cell disease

Stem-cell transplantation and genetic therapies offer potential cures for patients with sickle cell disease (SCD) but these options require advanced medical facilities and are expensive. Consequently, these treatments will not be available to the vast majority of patients suffering from this disease for many years. What is urgently needed now is an inexpensive oral drug in addition to hydroxyurea, the only successful drug approved by the FDA that inhibits sickle-hemoglobin polymerization. Here we report results of the first phase of our phenotypic screen of the 12,657 compounds of the Scripps ReFrame drug repurposing library using a recently developed high-throughput assay to measure sickling times following deoxygenation to 0% oxygen of red cells from sickle trait individuals. The ReFrame library is a very important collection because the compounds are either FDA-approved drugs or have been tested in clinical trials. From dose-response measurements, 106 of the 12,657 compounds exhibit statistically significant anti-sickling at concentrations ranging from 31 nM to 10 M. Compounds that inhibit sickling of trait cells are also effective with SCD cells. As many as 21 of the 106 anti-sickling compounds emerge as potential drugs. This estimate is based on a comparison of inhibitory concentrations with free concentrations of oral drugs in human serum. Moreover, the expected therapeutic effect for each level of inhibition can be predicted from measurements of sickling times for cells from individuals with sickle-syndromes of varying severity. Our results should motivate others to develop one or more of these 106 compounds into drugs for treating SCD. Significance StatementThe vast majority of patients suffering from sickle cell disease live in under-resourced countries. Consequently, advanced medical facilities required for curative therapies, such as stem cell transplantation and gene therapy, will be unavailable to them for a long time. Hydroxyurea, approved by the FDA in 1998, is the only effective drug that inhibits polymerization of the mutant hemoglobin S that stiffens and distorts ("sickles") red cells, the root cause of the pathology. What is urgently needed now for these patients are additional, inexpensive oral anti-sickling drugs. Our high throughput phenotypic screen of the ReFrame drug repurposing library reported here discovered 106 compounds that are anti-sickling. On a statistical concentration basis, as many as 21 are predicted to be potential drugs.

pharmacology and toxicology↗